Duchenne Muscular Dystrophy : MYODA clinical program

About Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a rare, X-linked recessive inherited disorder affecting 1 in 3,500 boys. DMD is the most common muscle dystrophy in children and has a fatal outcome.

DMD is due to the alteration of the dystrophin gene, which results in the absence of functional dystrophin, leading to progressive muscle weakness, but also to cardiac defects and impaired respiratory function, leading to premature death of patients before the age of 40. In the European Union, the prevalence of DMD is estimated at 0.81 per 10,000.

The absence of dystrophin makes the DAGC complex unstable and the membrane of the muscle fibres is severely weakened. Therefore, during muscle contraction, the fibres will become damaged, and will eventually die (necrosis). Muscle tissue regeneration phenomena are set up in parallel, starting from the stem cells of the muscle tissue (the satellite cells). When the regenerative mechanisms are exhausted, degeneration prevails, the muscle fibres are then replaced by connective tissue (fibrosis) and adipose tissue, resulting in a loss of muscle strength and an intolerance to exercise.

The first clinical signs of the disease develop during childhood. In fact, the first symptoms are usually reported before the age of 5. DMD evolves according to a very well described progression. The disease manifests itself first in the lower muscles. Around the age of 10 to 12, the use of a wheelchair becomes essential. The muscle tone of the trunk and arms gradually disappears, leading to complications (bronchopulmonary infections and ventilatory complications), as well as severe scoliosis. Around the age of 20, patients develop major respiratory and cardiac failures, which inexorably lead to death around the age of 30.

Proof of concept

Biophytis focused on a murine (mouse) model of Duchenne muscular dystrophy (mdx mouse), which has a mutation on the dystrophin gene, to demonstrate the beneficial effects of BIO101 in a context of myopathy. Untreated animals with myopathy (mdx) have very poor physical performance compared with control animals, which do not have the disease (C57Bl10). Mdx animals that receive a daily dose of Sarconeos administered orally show significant improvement in their physical performance with:

An increase in their running distance (exercise tolerance) by a factor of 2.4

The study of muscle histology of mice with myopathy shows that mdx mice exhibit inflammatory infiltration as well as areas of fibrosis compared to healthy muscle in C57Bl10 control mice. In a very interesting way, Biophytis has demonstrated that Sarconeos improves the muscular lesion profile. Indeed, daily treatment of mice with Sarconeos makes it possible to decrease the atrophy of the muscular fibers and the chronic inflammatory associated with fibrosis.

At the level of the heart, the analysis of molecular markers made it possible to show that the daily oral treatment of mdx mice by Sarconeos allows the reduction of markers of fibrosis (ctgf) as well as markers of cardiac hypertrophy (myh7 and bmp4), which are increased in Duchenne muscular dystrophy.

Effect of Sarconeos treatment on cardiac expression of markers of fibrosis (Ctgf) or cardiac hypertrophy (Myh7 and Bmp4) in mdx mice.

The beneficial functional effects observed in Sarconeos-treated animals are consistent with the results obtained with human cells from a patient with Duchenne muscular dystrophy. Indeed, Sarconeos is responsible for improving the differentiation of DMD myoblasts into myotubes. Moreover, in these same cells, Sarconeos induces significant activation of the AKT/mTOR and MAPK/ERK signaling pathways, respectively, involved in photosynthesis, proliferation, cell survival and in muscle regeneration and remodeling.

Effect of Sarconeos on three parameters concerning the differentiation of myoblasts from a DMD patient.

MYODA clinical program

The clinical programme of Sarconeos for Duchenne muscular dystrophy (DMD) will consist of 2 main studies: MYODA-PK and MYODA-INT.

The first study, MYODA-PK, is a combined SAD-MAD phase-1/2 paediatric study. It aims to evaluate the safety, pharmacokinetics and pharmacodynamics of the new paediatric form of Sarconeos in 27 paediatric patients (aged 2-18 years) after single ascending dose (SAD) administered orally and then multiple ascending doses (MAD) administered orally for 24 weeks. We plan 4 SAD doses, from which 3 will be tested in MAD. The safety and acceptability, adverse effects, and pharmacokinetic and pharmacodynamic profiles of BIO101 will be evaluated by age group. Sarconeos will be tested in its new formulation appropriate for paediatric patients.

The second study, MYODA-INT, is a phase-3, randomised, double-blind, placebo-controlled clinical trial. It aims to evaluate the safety and effectiveness of SARCONEOS in the new oral formulation to be administered to 120 paediatric patients aged 5-12 years with Duchenne muscular dystrophy. The treatment duration is 12 months. The primary endpoints will be for ambulatory patients, the change in North Star Ambulatory Assessment (NSAA), and for non-ambulatory patients, the change in performance upper limb (PUL) test score.

Sarconeos has obtained Orphan Drug Disease (ODD) designation from the FDA (Food and Drug Administration) and the EMA (European Medicines Agency), to treat Duchenne Muscular Dystrophy (DMD). As there are very few drug treatments available, Sarconeos is a drug candidate that has the potential to significantly slow the progression of the disease and could be used alone or in combination with genetic therapy, when the latter is available, in children with DMD. The status of ODD or orphan medication could give Sarconeos the advantages associated with orphan drug status, in particular the possibility of early registration (on the basis of a conditional authorisation) and protection for 7 to10 years after receiving the marketing authorisation.